Biweekly high-dose gemcitabine alone or in combination with capecitabine in patients with metastatic pancreatic adenocarcinoma: a randomized phase II trial.

BACKGROUND: Gemcitabine is an active antitumor agent in the treatment of advanced pancreatic cancer, and has shown potential synergistic activity with the oral fluoropyrimidine capecitabine in previous phase I/II trials. Based on this background and in order to define the therapeutic potential and tolerance of this combination more precisely, the present randomized multicenter phase II trial was initiated. PATIENTS AND METHODS: We prospectively randomized 83 patients to treatment with biweekly gemcitabine 2,200 mg/m(2) given as a 30 min intravenous infusion on day 1, or the same treatment plus oral capecitabine 2,500 mg/m(2) given from days 1 to 7. In both arms, chemotherapy was administered for a duration of 6 months unless there was prior evidence of progressive disease. The efficacy of the two treatment arms was evaluated according to standard criteria, i.e. objective response, progression-free survival (PFS) and overall survival (OS), as well as by analysis of clinical benefit response. RESULTS: The overall objective response rate among the 42 patients treated with gemcitabine alone was 14% compared with 7/41 (17%) among those treated with the combination arm. Similar to response rates, there was no apparent difference between the two groups in terms of median PFS (4.0 versus 5.1 months) and median OS (8.2 versus 9.5 months) in the gemcitabine and combination arm, respectively. Of 61 patients with tumor-related symptoms, who were considered evaluable for clinical benefit response, 10/30 (33%) and 15/31 (48.4%) experienced significant palliation in the gemcitabine and combination arm, respectively. Chemotherapy was well tolerated in both arms with only four versus six patients experiencing WHO grade 3 symptoms. Apart from the occurrence of hand-foot syndrome in 10 patients, no major increase in incidence and/or degree of adverse reactions was noted in the combination arm. CONCLUSIONS: Results of this trial suggest a fairly good therapeutic index for the combination of biweekly high-dose gemcitabine and capecitabine for the treatment of advanced pancreatic cancer. Despite a somewhat superior clinical benefit response rate, no advantage over single-agent gemcitabine, however, was noted in terms of objective efficacy parameters.     

Capecitabine plus oxaliplatin (CapOx) versus capecitabine plus gemcitabine (CapGem) versus gemcitabine plus oxaliplatin (mGemOx): final results of a multicenter randomized phase II trial in advanced pancreatic cancer.

BACKGROUND: To compare the efficacy and safety of three different chemotherapy doublets in the treatment of advanced pancreatic cancer (PC). PATIENTS AND METHODS: At total of 190 patients were randomly assigned to receive capecitabine 1000 mg/m(2) twice daily on days 1-14 plus oxaliplatin 130 mg/m(2) on day 1 (CapOx), capecitabine 825 mg/m(2) twice daily on days 1-14 plus gemcitabine 1000 mg/m(2) on days 1 and 8 (CapGem) or gemcitabine 1000 mg/m(2) on days 1 and 8 plus oxaliplatin 130 mg/m(2) on day 8 (mGemOx). Treatment cycles were repeated every three weeks. The primary end point was progression-free survival (PFS) rate at 3 months; secondary end points included objective response rate, carbohydrate antigen 19-9 response, clinical benefit response, overall survival and toxicity. RESULTS: The PFS rate after 3 months was 51% in the CapOx arm, 64% in the CapGem arm and 60% in the mGemOx arm. Median PFS was estimated with 4.2 months, 5.7 months and 3.9 months, respectively (P = 0.67). Corresponding median survival times were: 8.1 months (CapOx), 9.0 months (CapGem) and 6.9 months (mGemOx) (P = 0.56). Grade 3/4 hematological toxicities were more frequent in the two Gem-containing arms; grade 3/4 non-hematological toxicity rates did not exceed 15% in any arm. CONCLUSION: CapOx, CapGem and mGemOx have similar clinical efficacy in advanced PC. Each regimen has a distinct but manageable tolerability profile.     

培美曲塞或吉西他滨联合顺铂一线治疗晚期非小细胞肺癌的临床随机对照研究

目的:比较培美曲塞联合顺铂(PEM)方案与吉西他滨联合顺铂(GEM)方案一线治疗晚期非小细胞肺癌(NSCLC)的疗效及耐受性.方法:30例经组织学确诊的ⅢB期或Ⅳ期初治NSCLC患者随机分成PEM组和GEM组,每组各15例.结果:PEM组RR为40.0％,PFS为5.60个月,OS为18.07个月;GEM组RR为20.0％,PFS为6.50个月,OS为18.10个月,两组比较差异均无统计学意义,P值分别为0.182、0.431和0.516.肺腺癌中PEM组RR、PFS及OS均好于GEM组,但差异无统计学意义,P＞0.05.两组主要毒副反应均为骨髓抑制和胃肠道反应,PEM组患者Ⅲ/Ⅳ度血液学毒性发生率均低于GEM组患者,差异无统计学意义,P＞0.05.结论:培美曲塞联合顺铂一线治疗晚期非小细胞肺癌,特别是肺腺癌,疗效确切,耐受性良好.     

Gemcitabine concurrent with continuous infusional 5-fluorouracil in advanced biliary cancers: a review of the Princess Margaret Hospital experience.

BACKGROUND: Unresectable biliary tract cancer has a very poor prognosis. A combination of weekly gemcitabine plus continuous infusional 5-fluorouracil (5-FU) (GEM/CVI 5-FU) was evaluated as therapy for this cancer. PATIENTS AND METHODS: The charts of 27 patients with advanced biliary tract adenocarcinoma treated with GEM/CVI 5-FU at the Princess Margaret Hospital were evaluated for response, survival and toxicity. The treatment consisted of a 30-min infusion of gemcitabine at 900 mg/m(2) on days 1, 8 and 15 of a 28-day cycle plus 5-FU given via a peripherally inserted central line at 200 mg/m(2)/day continuously for 21 days, every 28 days. RESULTS: Objective responses were observed in nine patients (33%; 95% confidence interval 17% to 54%). An additional eight patients (30%) achieved stable disease for a median of 4 months (range 2.3-11). Median time to progression and overall survival were 3.7 and 5.3 months, respectively. Direct chemotherapy-related toxicity was mild, with only 11% grade > or =3 myelosuppression. Central venous catheter complications were common (26%). There were no treatment-related deaths. CONCLUSIONS: This study shows that GEM/CVI 5-FU is active and well tolerated in advanced and metastatic biliary tract cancers.     

Randomized phase II three-arm trial with three platinum-based doublets in metastatic non-small-cell lung cancer. An Italian Trials in Medical Oncology study.

BACKGROUND: Many patients with advanced non-small-cell lung cancer (NSCLC) do not tolerate cisplatin-based regimens because of its nonhemathological toxicity. PATIENTS AND METHODS: We evaluated the response rate safety of new platinum analogue regimens, randomizing 147 patients with nonoperable IIIB/IV NSCLC to (i) carboplatin (area under the curve = 5 mg min/ml) on day 1 plus gemcitabine (GEM) (1000 mg/m(2)) on days 1 and 8 for six cycles; (ii) same regimen for three cycles followed by docetaxel (Taxotere) (40 mg/m(2)) on days 1 and 8 plus GEM (1250 mg/m(2)) on days 1 and 8 for three cycles; (iii) oxaliplatin (130 mg/m(2)) on day 1 plus GEM (1250 mg/m(2)) on days 1 and 8 for six cycles. RESULTS: Intention-to-treat objective response rates were 25%, 25% and 30.6% in arms A, B and C, respectively. Median survival was 11.9, 9.2 and 11.3 months in arms A, B and C, respectively. Grade 3/4 neutropenia/anemia occurred in 29%/12.5%, 10%/16.5% and 8%/6% of arms A, B and C, respectively; grade 3/4 thrombocytopenia in 20.5%, 16.5% and 6%; grade 1/2 neurological toxicity in 43% of arm C. CONCLUSIONS: Oxaliplatin/GEM (arm C) had similar activity to carboplatin/GEM (arm A), but milder hematological toxicity and may be worth testing in a phase III study against carboplatin/GEM in patients not suitable for cisplatin. The sequential regimen gave no additional benefit.     

Cisplatin and gemcitabine first-line chemotherapy followed by maintenance gemcitabine or best supportive care in advanced non-small cell lung cancer: a phase III trial

PURPOSE: The primary objective of this randomized phase III study was to show significant difference in median time to progression (TTP) in patients with advanced NSCLC treated with single-agent gemcitabine maintenance therapy versus best supportive care following gemcitabine plus cisplatin initial first-line therapy. PATIENTS AND METHODS: Chemonaive patients with stage IIIB/IV NSCLC received gemcitabine 1,250 mg/m(2) (days 1 and 8) plus cisplatin 80 mg/m(2) (day 1) every 21 days. Patients achieving objective response or disease stabilization following initial gemcitabine plus cisplatin therapy were randomized (2:1 fashion) to receive maintenance gemcitabine (1,250 mg/m(2) on days 1 and 8 every 21 days) plus best supportive care (GEM arm), or best supportive care only (BSC arm). RESULTS: Between November 1999 and November 2002, we enrolled 352 patients (median age: 57 years; stage IV disease: 74%; Karnofsky performance status (KPS) >80: 41%). Following initial therapy, 206 patients were randomized and treated with gemcitabine (138) or best supportive care (68). TTP throughout the study period was 6.6 and 5 months for GEM and BSC arms, respectively, while values for the maintenance period were 3.6 and 2.0 months (for p < 0.001 for both). Median overall survival (OS) throughout study was 13.0 months for GEM and 11.0 months for BSC arms (p = 0.195). The toxicity profile was mild, with neutropenia being most common grade 3/4 toxicities. CONCLUSION: Maintenance therapy with gemcitabine, following initial therapy with gemcitabine plus cisplatin, was feasible, and produced significantly longer TTP compared to best supportive care alone. Further studies are warranted to establish the place of maintenance chemotherapy in patients with advanced NSCLC.     

Capecitabine combined with gemcitabine (CapGem) as first-line treatment in patients with advanced/metastatic biliary tract carcinoma

BACKGROUND: Biliary tract carcinoma is an aggressive cancer, with median survival rarely exceeding 6 months. There is currently no established palliative standard of care. A Phase II trial was conducted to study a combination of oral capecitabine and gemcitabine (CapGem) as first-line therapy in patients with advanced and/or metastatic biliary carcinoma. METHODS: Patients with unresectable or metastatic intrahepatic or extrahepatic biliary duct carcinoma and gallbladder carcinoma were enrolled. Eligible patients had histologically or cytologically confirmed, measurable adenocarcinoma and had not received prior therapy with capecitabine or gemcitabine. Treatment consisted of intravenous (i.v.) gemcitabine (1000 mg/m(2) on Days 1 and 8) plus oral capecitabine (650 mg/m(2) twice daily on Days 1-14) every 3 weeks for up to 6 cycles. Tumor response, survival, and safety were determined. RESULTS: A total of 44 patients were evaluable. Primary tumor sites were: intrahepatic (n = 14) and extrahepatic biliary duct (n = 16); gallbladder (n = 7); and ampulla (n = 7). Fourteen (32%) patients had a partial response and 15 (34%) patients had stable disease. Median time to disease progression and overall survival were 6.0 (range, 3.8-8.1) and 14 (range, 11.4-16.6) months, respectively. The 1-year survival rate was 58%. No Grade 4 adverse events were seen. Transient Grade 3 neutropenia/thrombocytopenia and manageable (almost invariably Grade 2) nausea, diarrhea, and hand-foot syndrome were the most common adverse events. CONCLUSIONS: CapGem is an active and well tolerated first-line combination chemotherapy regimen for patients with advanced/metastatic biliary tract carcinoma that offers a convenient home-based therapy.     

A randomized,multicenter, phase II study of vandetanib monotherapy versus vandetanib in combination with gemcitabine versus gemcitabine plus placebo in subjects with advanced biliary tract cancer: the VanGogh study

Vandetanib did not demonstrate any superiority alone or in combination with gemcitabine in the progression-free survival of patients affected by advanced biliary tract cancer compared with gemcitabine alone. The safety profile of vandetanib given (alone or in combination with gemcitabine) does not show any additional adverse events (AEs) or worsening of already known AEs.BackgroundThe management of biliary tract cancers (BTCs) is complex due to limited data on the optimal therapeutic approach. This phase II multicenter study evaluated the efficacy and tolerability of vandetanib monotherapy compared with vandetanib plus gemcitabine or gemcitabine plus placebo in patients with advanced BTC.Patients and methodsPatients were randomized in a 1 : 1 : 1 ratio to three treatment groups: vandetanib 300 mg monotherapy (V), vandetanib 100 mg plus gemcitabine (V/G), gemcitabine plus placebo (G/P). Vandetanib (300 mg or 100 mg) or placebo was given in single oral daily doses. Gemcitabine 1000 mg/m² was i.v. infused on day 1 and day 8 of each 21-day cycle. The primary end point was progression-free survival (PFS). Secondary end points were: objective response rate (ORR), disease control rate, overall survival, duration of response, performance status and safety outcomes.ResultsA total of 173 patients (mean age 63.6 years) were recruited at 19 centers across Italy. Median (95% confidence intervals) PFS (days) were 105 (72–155), 114 (91–193) and 148 (71–225), respectively, for the V, V/G and G/P treatment groups, with no statistical difference among them (P = 0.18). No statistical difference between treatments was observed for secondary end points, except ORR, which slightly favored the V/G combination over other treatments. The proportion of patients reporting adverse events (AEs) was similar for the three groups (96.6% in V arm, 91.4% in the V/G arm and 89.3% in the G/P arm).ConclusionsVandetanib treatment did not improve PFS in patients with advanced BTC. The safety profile of vandetanib did not show any additional AEs or worsening of already known AEs.Clinical trial numberNCT00753675.     

Gemcitabine and cisplatin versus mitomycin, ifosfamide, and cisplatin in advanced non-small-cell lung cancer: A randomized phase III study of the Italian Lung Cancer Project.

PURPOSE: To compare gemcitabine and cisplatin (GC) with mitomycin, ifosfamide, and cisplatin (MIC) chemotherapy in patients with stage IIIB (limited to T4 for pleural effusion and N3 for supraclavicular lymph nodes) or stage IV non-small-cell lung cancer (NSCLC). The end points were the evaluation of quality of life (QoL), response rates, survival, and toxicity. PATIENTS AND METHODS: Three hundred seven patients were randomized to receive either gemcitabine 1,000 mg/m(2) on days 1, 8, and 15 plus cisplatin 100 mg/m(2) on day 2, every 28 days, or mitomycin 6 mg/m(2), ifosfamide 3,000 mg/m(2), and mesna on day 1 plus cisplatin 100 mg/m(2) on day 2, every 28 days. The whole-blood cell count was repeated on day 1 in both arms and weekly in the GC arm before each gemcitabine administration. RESULTS: No major differences in changes in QoL were observed between the two treatment arms. The objective response rate was 38% in the GC arm compared with 26% in the MIC arm (P =.029). The median survival time was 8.6 months in the GC arm and 9.6 months in the MIC arm (P =.877, log-rank test). Grade 3 and 4 thrombocytopenia was significantly worse in the GC arm (64% v 28%, P <.001), whereas grade 3 and 4 alopecia was reported more commonly in the MIC arm (39% v 12%, P <. 001). CONCLUSION: We report an increased response rate without changes in QoL and a similar overall survival, time to progression, and time to treatment failure for the GC when compared with the MIC regimen in the treatment of advanced NSCLC.     

Docetaxel plus gemcitabine or docetaxel plus cisplatin in advanced pancreatic carcinoma: randomized phase II study 40984 of the European Organisation for Research and Treatment of Cancer Gastrointestinal Group.

PURPOSE: To define the efficacy and toxicity of docetaxel plus gemcitabine or docetaxel plus cisplatin for advanced pancreatic carcinoma. PATIENTS AND METHODS: Chemotherapy-naive patients with measurable disease and WHO performance status less than 2 were randomly assigned to receive 21-day cycles of gemcitabine 800 mg/m2 on days 1 and 8 plus docetaxel 85 mg/m2 on day 8 (arm A) or docetaxel 75 mg/m2 on day 1 plus cisplatin 75 mg/m2 on day 1 (arm B). Primary end points were tumor response and rate of febrile neutropenia grade. RESULTS: Of 96 randomly assigned patients (49 patients in arm A and 47 patients in arm B), 70 patients were analyzed for response (36 in arm A and 34 in arm B) and 89 patients were analyzed for safety (45 in arm A and 44 in arm B). Confirmed responses were observed in 19.4% (95% CI, 8.2% to 36.0%) of patients in arm A and 23.5% (95% CI, 10.7% to 41.2%) in arm B. In arm A, the median progression-free survival (PFS) was 3.9 months (95% CI, 3.0 to 4.7 months), median survival was 7.4 months (95% CI, 5.6 to 11.0 months), and 1-year survival was 30%. In arm B, the median PFS was 2.8 months (95% CI, 2.6 to 4.6 months), median survival was 7.1 months (95% CI, 4.8 to 8.7 months), and 1-year survival was 16%. Febrile neutropenia occurred in 9% and 16% of patients in arms A and B, respectively. CONCLUSION: Both regimens are well tolerated and show activity in advanced pancreatic carcinoma. The safety profile and survival analyses favor docetaxel plus gemcitabine for further evaluation.     

吉西他滨联合卡培他滨治疗41例复发或转移性胆管细胞癌的临床疗效和安全性观察

目的 观察吉西他滨联合卡培他滨治疗复发或转移性胆管细胞癌的临床疗效和安全性.方法 收集2000年3月至2004年12月间在南京军区福州总医院经病理确诊并符合入组条件的41例复发或转移性胆管细胞癌患者,给予吉西他滨联合卡培他滨方案化疗,观察近期疗效、远期疗效和安全性.结果 36例患者可评价疗效,其中完全缓解(CR)0例,部分缓解(PR)11例,病情稳定(SD)11例、病情进展(PD)14例;临床有效率为30.1%,临床受益率为61.1%.患者的中位生存时间和中位疾病进展时间分别为10个月和6个月.化疗后常见的毒副反应为胃肠道反应、乏力和手足综合征等,且以Ⅰ、Ⅱ级毒副反应居多.结论 卡培他滨联合吉西他滨治疗复发或转移性胆管细胞癌是安全和有效的,值得开展多中心临床协作研究来进一步探讨.     

A multicenter randomized phase III trial of vinorelbine/gemcitabine doublet versus capecitabine monotherapy in anthracycline- and taxane-pretreated women with metastatic breast cancer

BackgroundThe Breast Cancer Study Group of the Hellenic Oncology Research Group conducted a phase III trial of single-agent capecitabine versus the vinorelbine/gemcitabine doublet in patients with metastatic breast cancer (MBC) pretreated with anthracyclines and taxanes. The primary objective was to demonstrate superiority of combination treatment in terms of progression-free survival (PFS).Patients and methodsWomen with MBC were randomly assigned to receive either capecitabine (Cap arm: 1250 mg/m² twice daily, on days 1–14) or vinorelbine/gemcitabine doublet (VG arm: vinorelbine 25 mg/m²; gemcitabine 1000 mg/m²; both drugs on days 1 and 15).ResultsSeventy-four women were treated on each arm and median PFS was 5.4 versus 5.2 months (P = 0.736), for VG and Cap, respectively. Median overall survival was 20.4 months for the VG arm and 22.4 months for the Cap arm (P = 0.319). Overall response rate was 28.4% in the VG arm and 24.3% in the Cap arm (P = 0.576). Both regimens were generally well tolerated. Neutropenia and fatigue were more common with VG arm and hand–foot syndrome with Cap arm.ConclusionsThis trial failed to demonstrate superiority of vinorelbine/gemcitabine doublet over single-agent capecitabine in terms of PFS. Given the favorable toxicity and convenience of oral administration, single-agent capecitabine is recommended for compliant patients.     

Irinotecan plus gemcitabine results in no survival advantage compared with gemcitabine monotherapy in patients with locally advanced or metastatic pancreatic cancer despite increased tumor response rate.

PURPOSE: This phase III, randomized, open-label, multicenter study compared the overall survival associated with irinotecan plus gemcitabine (IRINOGEM) versus gemcitabine monotherapy (GEM) in patients with chemotherapy-naive, locally advanced or metastatic pancreatic cancer. PATIENTS AND METHODS: IRINOGEM patients received starting doses of gemcitabine 1,000 mg/m2 and irinotecan 100 mg/m2 given weekly for 2 weeks every 3-week cycle. GEM patients received gemcitabine 1,000 mg/m2 weekly for 7 of 8 weeks (induction) and then weekly for 3 of 4 weeks. The primary end point of the trial was survival. Secondary end points included tumor response, time to tumor progression (TTP), changes in CA 19-9, and safety. RESULTS: In each arm, 180 randomly assigned patients comprised the intent-to-treat population evaluated for efficacy; 173 IRINOGEM and 169 GEM patients were treated. Median survival times were 6.3 months for IRINOGEM (95% CI, 4.7 to 7.5 months) and 6.6 months for GEM (95% CI, 5.2 to 7.8 months; log-rank P =.789). Tumor response rates were 16.1% (95% CI, 11.1% to 22.3%) for IRINOGEM and 4.4% (95% CI, 1.9% to 8.6%) for GEM (chi2 P <.001). Median TTP was 3.5 months for IRINOGEM versus 3.0 months for GEM (log-rank P =.352). However, subset analyses in patients with locally advanced disease suggested a TTP advantage with IRINOGEM versus GEM (median, 7.7 v 3.9 months). CA 19-9 progression was positively correlated with tumor progression. The incidence of grade 3 diarrhea was higher in the IRINOGEM group but grade 3 to 4 hematologic toxicities and quality-of-life outcomes were similar. CONCLUSION: IRINOGEM safely improved the tumor response rate compared with GEM but did not alter overall survival.     

Preclinical and clinical evaluation of four gemcitabine plus carboplatin schedules as front-line treatment for stage IV non-small-cell lung cancer.

BACKGROUND: To explore the activity and tolerability of gemcitabine (GEM) and carboplatin (CBDCA) in non-small-cell lung cancer (NSCLC) we tested four administration sequences on H460 NSCLC cells, and at the same time performed a randomized phase II trial using analogous schedules. PATIENTS AND METHODS: GEM was given first in two in vitro sequences, and CBDCA first in the other two; interaction was quantified calculating a combination index. Eighty-eight chemotherapy-na?ve, stage IV NSCLC patients were randomly assigned to receive either: GEM (1000 mg/m(2)) on days 1 and 8 and CBDCA (AUC 5 mg.min/ml) on day 1, 4 h before GEM (arm A); same as arm A except CBDCA given 4 h after GEM (arm B); GEM on days 1 and 8 and CBDCA on day 2 (arm C); GEM on days 2 and 9 and CBDCA on day 1 (arm D). Courses were repeated every 21 days. RESULTS: In the preclinical study, CBDCA given before GEM produced a synergistic cytotoxic effect. Two complete and 29 partial responses occurred in 86 of 88 treated patients (intention-to-treat analysis 35%; 95% confidence interval 25.5% to 46.8%). One- and 2-year survivals were 44% and 11%, respectively. Grade 3/4 thrombocytopenia occurred in 11%; grade 3/4 neutropenia in 17%; and non-hematological toxicity was insignificant. Median survival was 11 months (range 7-18+), but better in patients receiving CBDCA first (arms A and D) (13 versus 9 months) than in patients receiving GEM first (arms B and C). The response was greater (50% versus 31%) in arm A than in the other arms. CONCLUSIONS: The CBDCA/GEM combination is safe and active against stage IV NSCLC. Our preclinical and clinical findings suggest that administration of CBDCA before GEM gives the better outcome.     

Cationic liposomal paclitaxel plus gemcitabine or gemcitabine alone in patients with advanced pancreatic cancer: a randomized controlled phase II trial

BackgroundPaclitaxel embedded in cationic liposomes (EndoTAG™-1; ET) is an innovative agent targeting tumor endothelial cells. This randomized controlled phase II trial evaluated the safety and efficacy of ET in combination with gemcitabine (GEM) in advanced pancreatic cancer (PDAC).Patients and methodsChemotherapy-naive patients with locally advanced or metastatic disease were randomly assigned to receive weekly GEM 1000 mg/m² or GEM plus twice-weekly ET 11, 22 or 44 mg/m² for 7 weeks. After a safety run-in of 100 patients, a second cohort continued treatment. End points included overall survival (OS), progression-free survival (PFS), tumor response and safety.ResultsTwo hundred and twelve patients were randomly allocated to the study and 200 were treated (80% metastatic, 20% locally advanced). Adverse events were manageable and reversible. Transient thrombocytopenia and infusion reactions with chills and pyrexia mostly grade 1 or 2 occurred in the ET groups. Disease control rate after the first treatment cycle was 43% with GEM and 60%, 65% and 52% in the GEM + ET cohorts. Median PFS reached 2.7 compared with 4.1, 4.6 and 4.4 months, respectively. Median OS was 6.8 compared with 8.1, 8.7 and 9.3 months, respectively.ConclusionsTreatment of advanced PDAC with GEM + ET was generally well tolerated. GEM + ET showed beneficial survival and efficacy. A randomized phase III trial should confirm this positive trend.     

Phase III trial of gemcitabine plus tipifarnib compared with gemcitabine plus placebo in advanced pancreatic cancer.

PURPOSE: To determine whether addition of the farnesyltransferase inhibitor tipifarnib (Zarnestra, R115777; Johnson and Johnson Pharmaceutical Research and Development, Beerse, Belgium) to standard gemcitabine therapy improves overall survival in advanced pancreatic cancer. PATIENTS AND METHODS: This randomized, double-blind, placebo-controlled study compared gemcitabine + tipifarnib versus gemcitabine + placebo in patients with advanced pancreatic adenocarcinoma previously untreated with systemic therapy. Tipifarnib was given at 200 mg bid orally continuously; gemcitabine was given at 1,000 mg/m(2) intravenously weekly x 7 for 8 weeks, then weekly x 3 every 4 weeks. The primary end point was overall survival; secondary end points included 6-month and 1-year survival rates, progression-free survival, response rate, safety, and quality of life. RESULTS: Six hundred eighty-eight patients were enrolled. Baseline characteristics were well balanced between the two treatment arms. No statistically significant differences in survival parameters were observed. The median overall survival for the experimental arm was 193 v 182 days for the control arm (P =.75); 6-month and 1-year survival rates were 53% and 27% v 49% and 24% for the control arm, respectively; median progression-free survival was 112 v 109 days for the control arm. Ten drug-related deaths were reported for the experimental arm and seven for the control arm. Neutropenia and thrombocytopenia grade > or = 3 were observed in 40% and 15% in the experimental arm versus 30% and 12% in the control arm. Incidences of nonhematologic adverse events were similar in two groups. CONCLUSION: The combination of gemcitabine and tipifarnib has an acceptable toxicity profile but does not prolong overall survival in advanced pancreatic cancer compared with single-agent gemcitabine.     

Cisplatin, gemcitabine, and vinorelbine combination therapy in advanced non-small-cell lung cancer: a phase II randomized study of the Southern Italy Cooperative Oncology Group.

PURPOSE: In a previous phase I study cisplatin (CDDP), gemcitabine (GEM), and vinorelbine (VNR) combination therapy was safe and very active in patients with non-small-cell lung cancer (NSCLC). This study was aimed at better defining the activity and toxicity of this regimen. PATIENTS AND METHODS: One hundred eleven chemotherapy-naive patients, age < or = 70 years, with stage IIIB or IV NSCLC and a performance status of 0 or 1 (Eastern Cooperative Oncology Group scale) were randomized to two treatment arms. Patients on arm A received CDDP 50 mg/m2, GEM 1,000 mg/m2, and VNR 25 mg/m2 on days 1 and 8 of an every-3-weeks cycle (57 patients). Patients on arm B received CDDP 80 mg/m2, epirubicin 80 mg/m2, and vindesine 3 mg/m2, all delivered on day 1 every 4 weeks, plus lonidamine orally 150 mg three times daily (54 patients). In December 1996, randomization was stopped early, and an additional 30 patients were treated with the experimental regimen to obtain a more accurate estimation of its activity rate. RESULTS: Among 87 patients who received the CDDP-GEM-VNR combination, four complete responses (CRs) and 46 partial responses (PRs) were observed, for an overall response rate of 57% (95% confidence interval [CI], 46% to 68%). Two CRs and 18 PRs were recorded among 54 patients on arm B, giving a 37% activity rate (95% CI , 24% to 51%). After a median follow-up duration of 19 months, the median progression-free and overall survival durations were 32 and 50 weeks in arm A, and 18 and 33 weeks in arm B, respectively. World Health Organization grade 3 to 4 neutropenia and thrombocytopenia occurred in 46% and 14% of patients in arm A and in 22% and 11% of those in arm B, respectively. Severe nonhematologic toxicity was uncommon in both arms. CONCLUSION: The CDDP-GEM-VNR combination is a highly effective treatment for patients with advanced NSCLC and has a manageable toxicity. A phase III trial comparing this new combination with both CDDP-VNR and CDDP-GEM regimens is underway.     

Capecitabine, an oral fluoropyrimidine carbamate with substantial activity in advanced colorectal cancer: results of a randomized phase II study.

PURPOSE: To evaluate in patients with advanced colorectal cancer (CRC) three treatment regimens of oral capecitabine in order to select the most appropriate regimen for testing in phase III. PATIENTS AND METHODS: Three capecitabine schedules were evaluated in a randomized phase II design: arm A, 1,331 mg/m(2)/d bid continuously; arm B, 2,510 mg/m(2)/d bid intermittently (2 weeks on/1 week off); and arm C, 1,657 mg/m(2)/d plus oral leucovorin 60 mg/d bid intermittently (2 weeks on/1 week off). RESULTS: One hundred nine patients were randomized; 39 patients were assessable for efficacy in arm A, 34 in arm B, and 35 in arm C. Patient characteristics were balanced in the arms. Confirmed tumor responses (partial response [PR] + complete response [CR]) were reported for eight patients with two CRs (21%; 95% confidence interval [CI], 9% to 36%) in arm A, eight patients with one CR (24%; 95% CI, 11% to 41%) in arm B, and eight patients with two CRs (23%; 95% CI, 10% to 40%) in arm C. Median times to progression (TTP) in arms A, B, and C were 127, 230, and 165 days, respectively. Overall, more toxicity was seen with capecitabine plus leucovorin, particularly diarrhea and hand-foot syndrome. There was no grade 3 or 4 marrow toxicity. CONCLUSION: Capecitabine offers a new, effective treatment option as an oral single agent in advanced CRC. Promising overall response rates were reported for all three regimens. The addition of leucovorin to the intermittent regimen had no marked effect on tumor response or median TTP. The intermittent single-agent capecitabine schedule is proposed for phase III evaluation, based on considerations of toxicity, dose-intensity, response rate, and TTP.     

Irinotecan plus raltitrexed vs raltitrexed alone in patients with gemcitabine-pretreated advanced pancreatic adenocarcinoma

There is no established second-line treatment for advanced pancreatic cancer after gemcitabine failure. In view of the urgent need for such therapy, and since preclinical and phase I clinical data suggest an encouraging, potentially synergistic activity between raltitrexed and irinotecan, the present randomised phase II study was initiated. A total of 38 patients with metastatic pancreatic adenocarcinoma, who progressed while receiving or within 6 months after discontinuation of palliative first-line chemotherapy with gemcitabine, were enrolled in this study. They were randomised to 3-weekly courses of raltitrexed 3 mg x m(-2) on day 1 (arm A) or irinotecan 200 mg x m(-2) on day 1 plus raltitrexed 3 mg x m(-2) on day 2 (arm B). The primary study end point was objective response, secondary end points included progression-free survival (PFS) and overall survival (OS), as well as clinical benefit response in symptomatic patients (n=28). In the combination arm, the IRC-confirmed objective response rate was 16% (three out of 19 patients had a partial remission; 95% CI, 3-40%), which was clearly superior to that in the comparator/control arm with raltitrexed alone, in which no response was obtained. Therefore, the trial was already stopped at the first stage of accrual. Also, the secondary study end points, median PFS (2.5 vs 4.0 months), OS (4.3 vs 6.5 months), and clinical benefit response (8 vs 29%) were superior in the combination arm. The objective and subjective benefits of raltitrexed+irinotecan were not negated by severe, clinically relevant treatment-related toxicities: gastrointestinal symptoms (42 vs 68%), partial alopecia (0 vs 42%), and cholinergic syndrome (0 vs 21%) were more commonly noted in arm B; however, grade 3 adverse events occurred in only three patients in both treatment groups. Our data indicate that combined raltitrexed+irinotecan seems to be an effective salvage regimen in patients with gemcitabine-pretreated pancreatic cancer. The superior response activity, PFS and OS (when compared to raltitrexed), as well as its tolerability and ease of administration suggest that future trials with this combination are warranted.     

Randomized phase II study of irinotecan plus mitomycin C vs. oxaliplatin plus mitomycin C in patients with advanced fluoropyrimidine/leucovorin-pretreated colorectal cancer

Introduction: Irinotecan and oxaliplatin are two new agents with promising activity in advanced colorectal cancer. Based on preclinical and clinical evidence that both drugs might act synergistically with mitomycin C, a randomized study using a 'pick the winner' design was undertaken to determine the effectiveness and tolerance of these two combination schedules in patients with fluoropyrimidine/leucovorin-pretreated advanced colorectal cancer. Patients and Methods: Sixty-four patients with metastatic colorectal cancer, who progressed while receiving or within 6 months after discontinuing palliative chemotherapy with fluoropyrimidines/leucovorin were enrolled onto this study. They were randomly assigned to treatment with irinotecan 120 mg/m ² on days 1+15 plus mitomycin C 8 mg/m2 on day 1 (arm A) or oxaliplatin 85 mg/m ² on days 1+15 plus mitomycin C 8 mg/m2 on day 1 (arm B). In both treatment arms, courses were repeated every 4 weeks. Results: The objective response rate in arm A is 7/33 (21.2%; 95% confidence interval, 9.0-38.9%) as compared to 5/31 in arm B (16.1%; 95% CI, 5.5-34.7%). Stable disease was noted in 48.5 vs. 45.2%, whereas the tumor progressed in 30.3 vs. 38.7%, respectively. Similar to the recorded response activities, the difference of the two combination regimens in terms of median time to progression (7.0 vs. 5.2 months) and overall survival (12.0 vs. 11.2 months) was only minor and clincally insignificant. The tolerance of treatment was acceptable in both arms, though severe adverse reactions requiring dose reductions (30 vs.16%) and treatment delays (22 vs. 13% of courses) were more commonly noted with irinotecan/mitomycin C. The most common toxicities in arm A were neutropenia (85%; WHO grade 3/4 in 33%), thrombocytopenia (52%), diarrhea (45%), emesis (52%) and alopecia (92%). In arm B, common toxicities included neutropenia (68%; grade 3/4 in 13%), thrombocytopenia (81%), emesis (52%), and peripheral neutropathy (48%). Conclusions: Both mitomycin C combination regimens seem to provide an acceptable therapeutic index in patients with fluoropyrimidine/leucovorin-pretreated metastatic colorectal cancer. In view of the increasing need for a broader chemotherapeutic armentarium for second-line therapy of this common malignant disease, both regimens may be worthwhile to undergo further clinical investigation.